Tissue distribution of 4-hydroxy-N-desmethyltamoxifen and tamoxifen-N-oxide.

Breast Cancer Research and Treatment
Jennifer GjerdeErnst A Lien

Abstract

Tamoxifen dosage is based on the one-dose-fits-all approach. The anticancer effect of tamoxifen is believed to be due to the metabolites, 4-hydroxytamoxifen (4OHtam), and 4-hydroxy-N-desmethyltamoxifen (4OHNDtam/endoxifen). These demethylated metabolites of tamoxifen have been associated with its side effects, whereas the effect mediated by tamoxifen-N-oxide (tamNox) is still poorly understood. Our objective was to improve the therapeutic index of tamoxifen by personalizing its dosage and maintaining serum tamoxifen metabolite concentrations within a target range. We examined the levels of tamoxifen, 4OHtam, 4OHNDtam, N-desmethyltamoxifen (NDtam), N-desdimethyltamoxifen (NDDtam), and tamNox in serum and in breast tumors specimens of 115 patients treated with 1, 5 or 20 mg/day of tamoxifen for 4 weeks before surgery in a randomized trial. Furthermore, the metabolism of tamNox in MCF-7 breast cancer cells was also studied. The concentrations of tamoxifen and its metabolites in tumor tissues were significantly correlated to their serum levels. Tumor tissue levels were 5-10 times higher than those measured in serum, with the exception of tamNox. In MCF-7 cells, tamNox was converted back to tamoxifen. In contrast to the tissue distr...Continue Reading

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Citations

Sep 3, 2013·Breast Cancer Research and Treatment·Ernst A LienJennifer Gjerde
Dec 18, 2013·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Nahla E El-Ashmawy, Rania M Khalil
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Jun 3, 2014·Toxicology·Mariana P C RibeiroJosé B A Custódio
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Aug 27, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Edwin J SquirewellMichael W Duffel
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Mar 10, 2019·Breast Cancer Research : BCR·Carrie B HruskaDeborah J Rhodes
Apr 17, 2020·Frontiers in Pharmacology·Lena Klopp-SchulzeCharlotte Kloft

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Methods Mentioned

BETA
electrophoresis

Software Mentioned

SAS
SPSS

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